Synaptic resilience is associated with maintained cognition during ageing

Declan King, Kris Holt, Jamie Toombs, Xin He, Owen Dando, Judith A. Okely, Makis Tzioras, Jamie Rose, Ciaran Gunn, Adele Correia, Carmen Montero, Hannah McAlister, Jane Tulloch, Douglas Lamont, Adele M. Taylor, Sarah E. Harris, Paul Redmond, Simon R. Cox, Christopher M. Henstridge, Ian J. DearyColin Smith, Tara L. Spires-Jones (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

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Abstract

Introduction: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing.

Methods: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate.

Results: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline.

Discussion: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.

Original languageEnglish
Number of pages15
JournalAlzheimer's and Dementia
Early online date22 Dec 2022
DOIs
Publication statusE-pub ahead of print - 22 Dec 2022

Keywords

  • Alzheimer's
  • ageing
  • cognition
  • synapse

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